CA2672114A1

CA2672114A1 - Use of epothilones in the treatment of osteoporosis and related diseases

Info

Publication number: CA2672114A1
Application number: CA002672114A
Authority: CA
Inventors: Jens Hoffmann; Sanna Kaekoenen; Ulrich Klar
Original assignee: Bayer Schering Pharma Aktiengesellschaft; Jens Hoffmann; Sanna Kaekoenen; Ulrich Klar
Current assignee: Bayer Pharma AG
Priority date: 2006-12-08
Filing date: 2007-12-05
Publication date: 2008-06-12
Also published as: US20080146626A1; MX2009006074A; CL2007003553A1; CN101553227A; WO2008068043A1; AU2007327767A1; UY30769A1; TW200829239A; EP2101765A1; EP1930004A1; KR20090087038A; IL198493A0; ZA200904755B; BRPI0719997A2; AR064214A1

Abstract

The present invention relates to the use of natural or synthetic Epothilones for the treatment prevention or alleviation of diseases caused by a dysbalance of osteoclast and osteoblast activity, especially osteoporosis.

Description

Use of Epothilones in the Treatment of Osteoporosis and related Diseases The present invention relates to the use of natural or synthetic Epothilones for the treatment or prophylaxis of diseases associated with a dysbalance of osteociast and osteoblast activity, especially osteoporosis.

Background of the invention Osteoporosis and related bone diseases are a common disease in the modern society (Sambrook et al., Osteoporosis, Lancet 2006 Jun 17, 367(9527):2001-8).
These diseases may be induced by age, by other diseases or they may be a side effect of drug therapies with existing drugs (e.g. Statins, aromatase inhibitors).
A number of treatments has been suggested, including bisphosphonate therapy, hormone therapy, parathyroid therapy.
However, these drug treatments cause significant side effects (e.g.
osteonecrosis caused by bisphosphonates (Bornstein et al., Schweiz Monatsschr. Zahnmed., 2006;
116 (10), 1035-1047).

There is therefore still need for new drugs for the treatment and prophylaxis of osteoporosis and related diseases.

Description of the Invention The present invention relates to the use of Epothilones in the treatment osteoporosis and related diseases.

The epothilones represent a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot., 1996, 49, 560-3; or Hoefle et al., Angew.
Chem.
[Applied Chem.], 1996, 108, 1671-1673). These cytotoxic antimitotic agents, block the mitotic spindle of a proliferating cell by binding to the spindle-peptide tubulin, and thus cause apoptosis (K.-H. Altmann, Curr. Opin. Chem. Biol., 2001, 5, 424-431).

The natural products Epothilone A and B as well as some of their synthetic derivatives have recently found interest in connection with the treatment of cancer, and a lot of work has been done on their synthesis (K. Nicolaou et al., Angew.
Chem., 1998, 110, 2120-2153) and the synthesis of modified structures.

WO 99/07692, WO 99/02514, WO 99/67252, and WO 2004/014919 disclose Epothilone derivatives, their synthesis and pharmaceutical use.

WO 00/66589 deals with the synthesis and pharmaceutical use of Epothilone derivatives having an alkenyl-, alkynyl-, or a cyclic ether containing substituent at the 6(10)-position of the macrocyclic ring.

WO 00/49021 discloses Epothilone derivatives with a halogen substituent in the 16(3)-position and their synthesis.

WO 00/71521 discloses a method for the synthesis of olefinic Epothilones.
WO 98/25929 deals with the manufacture of libraries of Epothilone analogs.

WO 99/43320 mentions, in a very general manner, the use of Epothilones for the treatment of cancer.

3 describes the use of Epothilones and Epothilone analogs in the treatment of brain diseases associated with proliferative processes.

WO 04/050089 describes the use of conjugates of Epothilones and Epothilone derivatives (as effectors) with suitable saccharides as saccharide derivatives (as recognition units) in the treatment of proliferative or angiogenesis-associated processes.

WO 2004/012735 describes the use of conjugates of Epothilones and Epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) in the treatment of proliferative or angiogenesis-associated processes.

4 describes the combination of Epothilones with a bisphosphonate, a platinum compound or a vasculostatic compound as use as combination therapy in the treatment of, inter alia, bone metastasis.

Finaly, WO 2006/032537 describes the use of Epothilones in the treatment of bone metastasis. Said application does not - however - disclose a treatment of bone diseases in patients without a tumour.

None of these publications, however, describe the use of Epothilones as monotherapy for the treatment of osteoporosis in cancer-free patients. In fact, there is no general or specific disclosure or suggestion in the prior art that pharmaceutically effective amounts of an Epothilone directly decrease osteoclast activity which is the underlying mechanism in the development of osteoporosis and related diseases.
Moreover there is no suggestion in the art that Epothilones in an amount well below the effective amount in cancer treatment may be effective in the treatment of osteoporosis and related diseases.

Thus the technical problem underlying the present invention is to provide compounds for the manufacture of medicaments for use in the treatment osteoporosis and related diseases. The solution to this technical problem is achieved by using Epothilones as described below for the manufacture of said medicaments.

It has now been found that unexpectedly Epothilones can inhibit osteociast activity, and thus show a beneficial effect in the treatment of osteoporosis and related diseases. Accordingly, the present invention provides the use of an Epothilone in the manufacture of medicaments for use as an inhibitor of osteoclast activity and is thus useful for the treatment of osteoporosis and related diseases.

The invention also provides a method of inhibiting osteociast activity in a patient in need of such treatment, which method comprises the administration of an effective amount of an Epothilone to said patient.

The invention also relates to methods of treating a disease associated with dysbalance of osteoblast and osteoclast activity, especially osteoporosis, by oral, parenteral, intravenious, rectal, or local, preferably inhalational, intravenous, or intraperitoneal, most preferably intravenous administration of an Epothilone.

In a particular embodiment of the present invention, the medicament containing the Epothilone is used to treat, prevent, or alleviate osteoporosis or related diseases.
The bone disease results from a dysbalance of osteoblast and osteoclast activity, cancer elsewhere in the body, especially an activation of osteociast activity, leading to bone hypodensity. The dysbalance of osteoblast and osteoclast activity may be the primary or secondary effect of the disease.

Thus in the frame of the present invention Epothilones are useful for the treatment, prevention or alleviation of diseases associated with a dysbalance of osteoblast and osteociast activity , especially for the treatment, prevention or alleviation of diseases associated with an activation of osteociast activity causing the dysbalance mentioned above, by inhibiting said osteoclast activity.

The following diseases are caused by dysbalance of osteoblast/osteoclast activity:
osteoporosis, osteonecrosis, osteoarthrosis, osteochondrosis, osteodystrophia rheumatic diseases, Spondylitis, Lupus and related auto-immune diseases, padget disease, arthrosis, periodontal disease or inflammatory diseases leading to osteoclast hyperactivityThus further embodiments of the invention are the use of epothilones to treat, prevent or alleviate osteoporosis, osteonecrosis, osteoarthrosis, osteochondrosis, osteodystrophia and the method to treat, prevent or alleviate said diseases.

Still further embodiments of the invention are the use of epothilones to treat, prevent or alleviate rheumatic diseases, Spondylitis, Lupus and related auto-immune diseases, padget disease, arthrosis, periodontal disease or inflammatory diseases leading to osteociast hyperactivity. A still further aspect of the invention therefore is the use of Epothilones to treat, prevent or alleviate T- , B-, and NK-killer cell mediated diseases, e.g. autoimmune diseases with bone pathology such as e.g.
psoriasis, psoriatic arthritis, SLE, rheumatoid arthritis, Graves disease, morbus Bechterev, MS.

Another aspect of the use of the present invention is the co-medication during the treatment of diseases with immunsuppressive agents. The immunsuppressive agents inhibit B- T- and/or NK-cells and may have the side effect that the proliferation of osteoclast precursor cells are inhibited or partly inhibited and the dysbalance as described above is thus caused by medication. For this purpose the composition of the present invention is also useful.

In addition one aspect of the invention therefore is also the use of the combination of immunosuppressive agents with an effective amount of an Epothilone for the purpose to treat, prevent or alleviate the side effect of the immunosuppressant, agents especially when causing a dysbalance of osteoblast and osteoclast activity.
Optionally one of the components of the combination or both may be in the form of a pharmaceutical formulation ready for use to be administered simultaneously, concurrently, separately or sequentially. The drugs may be administered independently of one another if necessary by different routes.

As immunosuppressive agents suitable for the combination are e.g.
glucocorticoids especially high dose applications, Natalizumab , Azathioprin, Mitoxanthron, Mycophenolatmofetil, cyclosporins such as e.g. Cyclosporin A, Cacineurininhibitors such as Tacrolimus, Sirolimus, Everolimus, Cyclophosphamid, or Methotrexat, Fingolimod, CellCept, Myfortic, Anti-T-Lymphozytenglobulin, Anti-CD3-Antibody Muromonab Anti-CD25-Antikorper such as Basiliximab and Daclizumab Anti-TNF-a-Antik6rper such as Infliximab and Adalimumab .

A further aspect of the invention is the method of treating, preventing or alleviating said diseases. A preferred aspect of the invention is the use as defined in the claims for the treatment of the diseases mentioned in claims 1-6.

Another aspect of the invention is the use as defined in the claims for the treatment or prophylaxis of the diseases mentioned in claims 1-6.

Another aspect of the invention is the inhibition of inflammatory cells causing a dysbalance of osteoblast and osteoclast activity with Epothilones.

For the purposes of the present invention, an Epothilone is defined as a cyclic molecule with a 16-membered ring and variable substituents and pharmaceutical activity as a cytostatic agent that binds to tubulin (Asnes et al., Anal.
Biochem. 1979, 98, 64-73; Job et al., Cellular Pharmacol. 1993, I(Suppl. I), S7-S10; Lichtner et al., PNAS 2001, 98, 11743-11748). This definition includes natural (especially Epothilone A, Epothilone B (also referred to as EPO-906), Epothilone C, Epothilone D (also referred to as Kos-862), Epothilone E and Epothilone F) as well as semi-synthetic and synthetic Epothilones as described in the references cited above and some others. Examples for semi-synthetic and synthetic Epothilones are BMS-247550, BMS-310705, Ixabepilone, ABJ-879, Fludelone, KOS-1584, KOS-1803, and ZK-EPO, the structures of which are in the public domain and well known to the expert in the art.

For the purpose of this application the term "Epothilone" also includes Epothilone conjugates, Epothilone antibody conjugates and Epothilone pro-drugs such as e.g.
those described in WO 04/050089 , WO 2004/012735, DE 10234975 or WO
2005/074901 may be used for the present invention and are incorporated by reference herein.

One further aspect of the invention is the use according to the claims wherein the Epothilone is present in form of a pro-drug or an conjugate, especially an antibody conjugate. The group of Epothilones includes Epothilones wherein the Epothilone molecule contains a lactone or a lactame moiety, one aspect are Epothilones containing a lactame moiety, especially preferred are the lactone containing Epothilones.

Preferred Epothilones for use in the present invention are compounds of the general formula (I):

w R4b OH
R4a R3 Rla Rlb R2b Y R2a OH
Z (1) in which R'a, R'b are each independently hydrogen, Cl-Clo alkyl, aryl, aralkyl, or together form a-(CH2)m-group where m is 2 to 5;

R2a, R2b are each independently hydrogen, Cl-Clo alkyl, aryl, aralkyl, or together form a-(CH2)n-group where n is 2 to 5, or are C2-C10 alkenyl or C2-C10 alkynyl;

R3 is hydrogen, Cl-Clo alkyl, aryl or aralkyl;

R4a, R4b are each independently hydrogen, Cl-Clo alkyl, aryl, aralkyl, or together form a-(CH2)P- group where p is 2 to 5;

R5 is hydrogen, Cl-Clo alkyl, aryl, aralkyl, CO2H, CO2aIkyl, CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2NH(alkyl), CH2N(alkyl)2, CH2NH(acyl), CH2N(acyl)2 or CH2HaI;

R6, R' are each hydrogen, or together form an additional bond, or together form an epoxy function;

G is O or CH2;

D-E together is a group -H2C-CH2-, -HC=CH-, -C-C-, -CH(OH)-CH(OH)-, -CH(OH)-CH2-, -CH2-CH(OH)-, -CH2-O-, -O-CH2-, or / 0 \ , whereby if G is 0 then D-E is not CH2-O; or HC-CH
D-E-G together is a group H2C-CH=CH or a group CH=CH-CH2;

W is a group C(=X)R8, or is a bi- or tricyclic aromatic or heteroaromatic radical;

X is O, or two groups OR20, or a C2-C10 alkylenedioxy group (which may be straight or branched), or H and the group OR9, or a group CR10R";

R8 is hydrogen, Cl-Clo alkyl, aryl, aralkyl, halogen, CN;
R9 is hydrogen or a protecting group PGX;

R10, R" are each independently hydrogen, Cl-C2o alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7-membered carbocyclic ring;

Z is O
or H and the group OR12;

R12 is hydrogen or a protecting group PGZ;

A-Y is a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O), or NR21-S02;

WO 2008/068043 - $ - PCT/EP2007/010789 R20 is a Cl-C20 alkyl group;

R21 is hydrogen, or Cl-C10 alkyl;

PGx, PGz is CI-C20 alkyl, C4-C7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, Cl-C20 acyl, aroyl, Cl-C20 alkylsulfonyl, arylsulfonyl, tri(Cl-C20 alkyl)silyl, di(Cl-C20 alkyl) arylsilyl, P-C20 alkyl) diaryisilyl, or tri(aralkyl)silyl;

as a single stereoisomer or a mixture of different stereoisomers, and/or as a pharmaceutically acceptable salt thereof.

Another preferred embodiment for the use according to the invention are Epothilones of general formula (I) for use in the present invention :

R4b w OH
R4a R3 Rla Rlb R2b Y R2a OH
Z
wherein R'a, R'b are each independently hydrogen, Cl-C10 alkyl, aryl, aralkyl, or together form a-(CH2)m-group where m is 2 to 5;

R2a, R2b are each independently hydrogen, Cl-C10 alkyl, aryl, aralkyl, or together form a-(CH2)n group where n is 2 to 5, or are C2-C10 alkenyl or C2-Cl0 alkynyl;

R3 is hydrogen, Cl-C10 alkyl, aryl or aralkyl;

R4a, R4b are each independently hydrogen, Cl-C10 alkyl, aryl, aralkyl, or together form a-(CH2)P group where p is 2 to 5;

R5 is hydrogen, Cl-Clo alkyl, aryl, aralkyl, CO2H, CO2aIkyl, CH2OH, CH2OaIkyl, CH2Oacyl, CN, CH2NH2, CH2NH(alkyl), CH2N(alkyl)2, CH2NH(acyl), CH2N(acyl)2 or CH2HaI;

R6, R' are each hydrogen, or together form an additional bond, or together form an epoxy function;

G is O or CH2;

D-E together is a group -H2C-CH2-, -HC=CH-, -C-C-, -CH(OH)-CH(OH)-, -CH(OH)-CH2-, -CH2-CH(OH)-, -CH2-O-, -O-CH2-, or / 0 \ , whereby if G is 0 then D-E is not CH2-0; or HC-CH
D-E-G together is a group H2C-CH=CH or a group CH=CH-CH2;

W is a group C(=X)R8, or is a bi- or tricyclic aromatic or heteroaromatic radical;

X is O, or a group CR'oR";

R 8 is hydrogen, Cl-Clo alkyl, aryl, aralkyl, halogen, CN;

R10, R" are each independently hydrogen, Cl-C2o alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7-membered carbocyclic ring;

Z is O
or H and the group OR12;

R12 is hydrogen or a protecting group PGZ;

A-Y is a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O), or NR21-S02;
R21 is hydrogen, or Cl-Clo alkyl;

PGZ is Cl-C20 alkyl, C4-C7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, Cl-C20 acyl, aroyl, Cl-C20 alkylsulfonyl, arylsulfonyl, tri(Cl-C20 alkyl)silyl, di(Cl-C20 alkyl) aryisilyl, (Cl-C20 alkyl) diarylsilyl, or tri(aralkyl)silyl;

as a single stereoisomer or a mixture of different stereoisomers, and/or as a pharmaceutically acceptable salt thereof. ) Further preferred Epothilones for use in the present invention are compounds of the general formula (I):

w R4b OH
R4a R3 Rla Rlb R2b Y R2a OH
Z
in which A-Y is O-C(=O);
D-E is H2C-CH2;
G is CH2;

Z is O;

R'a, R'b are both Cl-Clo alkyl or together form a -(CH2)m- group where m is 2 or 3;
R2a, R2b are each independently hydrogen, Cl-Clo alkyl, C2-CIo alkenyl, or C2-Clo alkynyl;

R3 is hydrogen;

R4a, R4b are each independently hydrogen or Cl-Clo alkyl;
R5 is Cl-Clo alkyl.

Further preferred Epothilones for use in the present invention are compounds of the general formula (I):

wherein A-Y is O-C(=O);

D-E is H2C-CH2;

G is CH2;
Z is O;

R'a, R'b are both Cl-Clo alkyl or together form a-(CH2)m- group where m is 2 or 3;
R2a, R2b are each independently hydrogen, Cl-Clo alkyl, C2-Clo alkenyl, or C2-Clo alkynyl;

R3 is hydrogen;

R4a, Rab are each independently hydrogen or Cl-Clo alkyl;

R5 is Cl-Clo alkyl and all other residues have the meaning as indicated above as stated also in claim 10.

More preferred Epothiloneas are those in which:

R2a, R2b are each independently hydrogen, C2-Clo alkenyl or C2-Clo alkynyl;
R6, R' together form an epoxy function or an additional bond; and W is a 2-Methyl-benzothiazol-5-yl radical, a 2-Methyl-benzoxazol-5-yl radical, or a Quinoline-7-yl radical.

More preferred are Epothilones of formula (I) wherein:

R2a, R2b are each independently hydrogen, C2-Clo alkenyl or C2-Clo alkynyl;
R6, R' together form an epoxy function or an additional bond; and W is a 2-Methyl-benzothiazol-5-yl radical, a 2-Methyl-benzoxazol-5-yl radical, or a Quinoline-7-yl radical and all other residues have the meaning as indicated in claim 11.

Such Epothilones are for example:

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-en-1 -yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S,7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-en-1-yi)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S, 1 3E/Z, 1 6S)-4,8-dihydroxy-1 6-(2-methyl-benzothiazol-5-yl)-1 -oxa-9,1 3-d i methyl-5,5-(1,3-tri m ethyl e n)-7-(p ro p-2-e n- 1 -yl)-cyclohexadec-1 3-ene-2,6-dione;

(1 S/R,3S, 7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1,3-trimethylen)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S, 1 3E/Z, 1 6S)-4,8-dihydroxy-1 6-(2-methyl-benzothiazol-5-yl)-1-oxa-5, 5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R, 3S,7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-in-1-yi)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(chinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-( pro p-2-e n- 1 -yi)-cyclohexadec-1 3-ene-2,6-dione;

(1 S/R, 3S, 7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-en-1-yl)-3-(chinolin-2-yi)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]
heptadecane-5,9-dione;

(1 S,3S,7S,10R,11 S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yI)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]
heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-1 6-(2-methyl-benzothiazol-5-yl)-1 -aza-5,5,9,13-tetramethyl-7-(prop-2-en-1 -yl)-cyclohexadec-1 3-ene-2,6-dione; and (1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.

One aspect of the invention are Epothilones selected from the list consisting of:
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-en-1 -yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S, 7R,8S,9S,13E/Z,16S)-4,8-dihyd roxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S, 7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-en-1 -yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-1 6-(2-methyl-benzothiazol-5-yl)-1-oxa-9,13-dimethyl-5,5-(1, -oxa-9,13-dimethyl-5,5-(1,3-trimethy cyclohexadec-1 3-ene-2,6-dione;

(1 S/R,3S, 7S,10R,11 R,12S,16R/S)-7,11-d ihyd roxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1,3-trimethylen)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(1 S,3S,7S,10R,11 S,12S,16R)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(chinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(chinolin-2-yl)-8,8,12,16-tetramethyl-4,17-d ioxabicyclo[14.1.0]
heptadecane-5,9-dione;

(1 S,3S,7S,10R,11 S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]
heptadecane-5,9-dione;

(4S, 7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5, 5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione; and (1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-d ione.

Another group of Epothilones which are preferred are Epothilones in which:
R2a, R2b are each independently hydrogen, or Cl-Clo alkyl;

R6, R' together form an epoxy function or an additional bond;
W is a group C(=X)R8;

X is a group CR'oR";

R8 is hydrogen, halogen, or Cl-Clo alkyl; and R10, R" are hydrogen/2-methyl-thiazol-4-yl, hydrogen/2-pyridyl, hydrogen/2-methylamine-thiazol-4-yl, or hydrogen/2-methylsulfanyl-thiazol-4-yl.
Another group of Epothilones which are preferred are Epothilones of formula (I) wherein:

R2a, R2b are each independently hydrogen, or Cl-Clo alkyl;

R6, R' together form an epoxy function or an additional bond;
W is a group C(=X)R8;

X is a group CR10R";

R8 is hydrogen, halogen, or Cl-Clo alkyl; and R10, R" are hydrogen/2-methyl-thiazol-4-yl, hydrogen/2-pyridyl, hydrogen/2-methylamine-thiazol-4-yl, or hydrogen/2-methylsulfanyl-thiazol-4-yl and all other residues have the meaning as defined in claim 11.

This group of Epothilones may be exemplified by the following examples:

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-d ihyd roxy-10-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-1 2,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-d ione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-propyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S, 7R,8S,9S,13E/Z,16S(Z))-4,8-dihyd roxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R, 3S(Z), 7S,10R,11 S, 1 2S, 1 6R/S)-7,1 1 -dihyd roxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S, 7R,8S,9S,13E/Z,16S(Z))-4,8-d ihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl )-1-oxa-5, 5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R, 3S(Z), 7S,10R,11 S,12S,16R/S)-7,11-d ihyd roxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-12,16-d imethyl-10-ethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-propyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylen)-12,16-d imethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylen)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-1 3-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-10,12,16-dimethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione; and (1 S/R,3S(Z),7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione.

A still further preferred group of Epothilones are those in which R2a, R2b are each independently hydrogen, C2-C10 alkenyl or C2-C10 alkynyl;
R6, R7 together form an epoxy function or an additional bond;

W is a group C(=X)R8;
X is a group CR10R";

R 8 is hydrogen, halogen, or Cl-Clo alkyl; and R10, R" are hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl.
A still further preferred group of Epothilones are those wherein R2a, R2b are each independently hydrogen, C2-C10 alkenyl or C2-C10 alkynyl;
R6, R' together form an epoxy function or an additional bond;

W is a group C(=X)R8;
X is a group CR'oR";

R 8 is hydrogen, halogen, or Cl-Clo alkyl; and R10, R" are hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl.
Examples of this group are:

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-d ione;

(1 S/R,3S(E),7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-in-1 -yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yi)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S( E),7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(but-3-in-1-yl )-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(1 S/R,3S( E),7S,10R,11 R,12S,16R/S)-7,11-d ihyd roxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(1 S/R,3S(E),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methylthiazol-4-yI)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-in-1 -yl)-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicycio[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methylthiazol-4-yI)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione; and (1 S/R,3S(Z),7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione.

Another prefered group of Epothilones are those in which A-Y is NR21-C(=O).

In a further embodiment the Epothilone according to claim 10 or 11 is selected from the group consisting of (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11S,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yI)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(1 S/R,3S, 7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8, 8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-9,13-dimethyl-5,5-(1,3-trimethylen)-7-(prop-2-en-1 -yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1,3-trimethylen)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tet ra m eth yl-7-( p ro p-2-e n-1-yl )-cyc l o h exad e c-13-e n e-2 , 6-d i o n e;

(1 S/R,3S,7S,10R,11 R, 1 2S, 1 6R/S)-7,1 1 -dihydroxy-1 0-(prop-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S, 1 3E/Z, 1 6S)-4,8-dihydroxy-1 6-(1,2-dimethyl-1 H-benzoimidazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-en-1-yl)-3-(1,2-dimethyl-1 H-benzoimidazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S, 7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S,7S,10R,11 S,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, (1 S/R,3S,7S,10R,11 R,12S,16R/S)-7,11-d ihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-(2-methyl-1,3-thiazol-4-yl)prop-1 -en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione , (1 S,3S(E),7S,10R,11 S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-(2-methyl-l,3-thiazol-4-yl)prop-1-en-2-yl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione , (4S,7R,8S,9S,13Z,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-oxacyclohexadec-l3-ene-2,6-dione , (4S,7R,8S,9S,10E,13Z,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-oxacyclohexadec-10,13-diene-2,6-dione , (4S,7R,8S,9S,10E,13Z,16S(E))-4,8-dihydroxy-5,5,7,9-tetramethyl-l3-trifluormethyl-16-[1-(2-methyl-l,3-thiazol-4-yl)prop-1-en-2-yl]-oxacyclohexadec-10,13-diene-2,6-dione , (1 S,3S(E),7S,10R,11 S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-(2-methylsulfanyl-l,3-thiazol-4-yl)prop-l-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione as a single stereoisomer or a mixture of different stereoisomers, and / or as a pharmaceutically acceptable salt thereof.

The most preferred Epothilone is: 7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1 -yl)-8,8,12,16-tetramethyl-4,17-d ioxabicyclo[14.1.0]heptadecane-5,9-dione.

The name of the most preferred Epothilone 7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione includes any of its diastereoisomers, especially preferred is (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.
The term "alkyl" as used herein refers to straight or branched alkyl groups, e.
g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, neopentyl, heptyl, or decyl. Alkyl groups can be perfluorated or substituted by one to five substituents selected from the group consisting of halogen, hydroxy, Cl-C4 alkoxy, or C6-C12 aryl (which can be substituted by one to three halogen atoms).

The term "alkenyl" as used herein refers to a straight or branched chain monovalent or divalent radical, containing at least one double bond and having from two to ten carbon atoms, e.g., ethenyl, prop-2-en-1-yl, but-l-enyl, pent-1-enyl, penta-1,4-dienyl, and the like including isomers having an E- or Z-configurated double bond such as e.g. vinyl, propen-1-yl, propen-2-yl (Allyl), but-l-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl.

The term "alkynyl" as used herein refers to a substituted or unsubstituted straight or branched chain monovalent or divalent radical, containing at least one triple bond and having from two to ten carbon atoms, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-l-ynyl, pent-3-ynyl, and the like.

Alkenyl and alkenyl groups can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO2H, -CO2AIkyl, -NH2, -NO2, -N3, -CN, Cl-C20 acyl, or CI-C20 acyloxy.

The term "aryl" as used herein refers to an aromatic carbocyclic or heterocyclic moiety containing five to 14 ring atoms, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, chinolyl, or thiazolyl. Aryl groups can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO2H, -CO2AIkyI, -NH2, Alkyl-NH2, Cl-alkyl-thiolanyl, -NO2, -N3, -CN, CI-C20 alkyl, CI-C20 acyl, or Cl-C20 acyloxy.
The heteroatoms can be oxidized, if this does not cause a loss of aromatic character, e.
g., a pyridine moiety can be oxidized to give a pyridine N-oxide.

The term "aralkyl" as used herein refers to a group which can contain up to 14 atoms in the aryl ring (preferred five to ten) and one to eight carbon atoms in the alkyl chain (preferred one to four), e.g., benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, or pyridylpropyl. The rings can be substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, -CO2H, -CO2AIkyl, -NH2, -NO2, -N3, -CN, Cl-C20 alkyl, Cl-C20 acyl, or Cl-C20 acyloxy.

The protecting groups PGZ can be alkyl- and/or aryl-substituted silyl moieties, Cl-C20 alkyl, C4-C7 cycloalkyl, which may contain an oxygen atom in the ring, aryl, aralkyl, Cl-C20 acyl, aroyl, alkyl- or aryisulfonyl. Groups which can be easily be removed from the molecule are preferred, e.g., methoxymethyl, methoxyethyl, polyethylene glycol, ethoxyethyl, tetrahydropyranyl, tetra hyd rofu ra nyl, trimethylsilyl, triethylsilyl, t-butyidimethylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, as well as alkylsulfonyl or aryisulfonyl. Preferred acyl groups are formyl, acetyl, propionyl, pivaloyl, butyryl, or benzoyl, which all can be substituted by one or more amino and/or hydroxy moieties:

In one aspect of the invention the compounds defined in formula I as well as their salts, solvates and solvates of salts are useful for the use of the invention, especially compositions of the salts, solvates and salts of solvates of the compounds disclosed in the examples are one aspect of the invention.

The term physiologically unobjectable salts includes addition salts of mineral acids, carbonic acids, sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluoisulfonic acid, benzenesulfonic acid, naphthalinesulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, pivalinic acid, maleic acid, succinic acid and benzoic acid.

In addition the term physiologically unobjectable salts includes salts of commonly suitable bases, e.g. salts of alkalimetall (e.g.. sodium- and potassium salts), alkaline earth salts (e.g. calcium- and magnesium salts) and ammonium salts, derivatized from NH3 or organic amines with 1 to 16 carbon atoms, e.g. ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, prokaine, dibenzylamine, N-methylmorpholin, arginin, lysin, ethylendiamine and N-methylpiperidin.

The term "prodrug" includes compounds which can also be biologically active or inactive, but are at least converted into the biologically active compounds according to the invention during their presence in the body by e.g. metabolic or hydrolytic mechanisms.

The synthesis of the compounds listed above is described in the international patent applications WO 99/07692, WO 00/49021, WO 03/041068, WO 03/041063, WO 00/66589, WO 04/050089 and WO 2004/012735 which are incorporated herein by reference.

For the use according to the invention, the compounds can be formulated by methods known in the art. Compositions for the oral, rectal, parenteral or local application can be prepared in the form of tablets, capsules, granulates, suppositories, implantates, sterile injectable aqueous or oily solutions, suspensions or emulsions, aerosols, salves, creams, or gels, retard preparations or retard implantates or even coated catheters or coated stents. The compounds may also be administered by implantable dosing systems.

The pharmaceutical active compound(s) can thus be mixed with adjuvants known in the art, such as gum arabic, talcum, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj , magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives, and flavors.

The compounds can be used in the form of their clathrates of a-, (3-, or y-cyclodextrin or of substituted a-, (3-, or y-cyclodextrines, or in the form of a liposomal composition, in particular a liposomal composition comprising a polyethyleneglycol(PEG)-derivatized lipid. The compound may also be used in the form of a nanoformulation.

The term "therapeutically effective amount" as used herein refers to that amount of a compound of the invention which, when administered to an individual in need thereof, is sufficient to effect treatment, as defined below, for osteoporosis and related diseases. The amount which constitutes a "therapeutically effective amount"
will vary depending on the compound, the disease and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. It has to be appreciated that generally the "therapeutically effective amount" for a given Epothilone in the treatment of osteoporosis and related diseases is much lower than for the treatment of cancer - including bone metastasis - with the same Epothilone - it may be up to 100 times lower. All tests carried out with epothilones demonstrate that osteoclast activity has significantly been inhibited while no cytotoxic effect could be seen. It is therefore evident that treatment of osteoporosis and related diseases is not accompanied with any known side effect of the used epothilone.

The invention also relates to pharmaceutical compositions containing one or more of the pharmaceutically active compounds listed above, and their use for the treatment and in the methods in accordance with the present invention.
Preferably, one dose unit of these compositions contains about 0.0001-10 mg of the pharmaceutically active compound(s). The dosage for the use according to the invention for a human is about 0.0001-10 mg per day; a preferred dosage is about 0.001 -7 mg per day; a more preferred dosage is about 0.01-5 mg per day.

Compounds of the present invention have demonstrated positive results in osteoporosis treatment in animal models. The compounds of the present invention can be tested for utility through clinical trials, wherein the compounds are administered to human osteoporosis patients.

Examples:

The invention is demonstrated in the following examples which are not meant to limit the invention in any way:

Example 1 The objective of this study is to investigate the effects of selected test compounds selected on resorbing activity of human osteoclasts in vitro. Bone resorption is studied using a model where human osteoclast precursor cells derived from bone marrow are cultured for 7 days on bovine bone slices and allowed to differentiate into bone-resorbing osteoclasts. At day 7, the culture medium is changed, the test compounds are added, and the formed mature osteoclasts are allowed to resorb bone in an additional 3-day culture period. Tartrate-resistant acid phosphatase isoform 5b activity (TRACP 5b) is measured from the culture medium collected at day 7 as an index of the number of osteoclasts formed in each well during the differentiation period. After the totally 10 days culture period, C-terminal cross-linked telopeptides of type I collagen (CTX) are quantitated from the culture medium as an index of bone resorption. The results are expressed as the resorption index (CTX at day 10/TRACP 5b at day 7), which describes the mean activity of a single osteociast.
In each test, a baseline group without test compounds is included to obtain a baseline value. E64, an inhibitor of cathepsin enzymes and osteoclastic bone resorption, is added to control cultures to demonstrate that the test system can detect inhibition of bone resorption. The study is approved if the results of the control group are significantly different from the results of the baseline group. The test system can also be modified by adding the test compounds at the beginning of the culture period to study if the test compounds affect osteoclast differentiation.
Osteoprotegerin is used as a reference inhibitor of osteoclast differentiation in such cultures.

Test compounds The primary test compound used in this example is (1 S,3S,7S,10R,11 S,12S,16R)-7,11-d ihyd roxy-3-(2-methyl-benzothiazol-5-yl)-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (referred to as EPO-477) Control Substances E64 (catalogue number E3132, obtained from Sigma, St Louis, MO, USA) is used as a reference inhibitor of bone resorption.

Osteoprotegerin (OPG, catalogue number 450-14, obtained from PeproTech EC Ltd, London, UK) is used as a reference inhibitor of osteoclast differentiation, when necessary.

Description of the test system used The method of osteoclast culture on bone slices was originally described by Boyde and co-workers (1984) and by Chambers and co-workers (1984). The rate of bone resorption in the cultures was originally determined by counting the number of resorption pits on each bone or dentine slice using a microscope with phase contrast objectives (Sundquist et al. 1990). Later, the pits were visualized using Wheat Germ Agglutinin lectin that specifically binds to the resorbed area in bone (Selander et al.
1994), making it possible to quantitate the total resorbed area using a microscope and computer-assisted image analysis system (Laitala and Vaananen 1994, Hentunen et al. 1995). These methods have two disadvantages: They are time-consuming and they can not detect differences in the depth of the resorption pits, which may cause false results. Pharmatest uses a commercially available method (CrossLaps for cultures, Nordic Bioscience, Herlev, Denmark) to detect the amount of bone collagen degradation products released into the culture medium as an index of bone resorption (Bagger et al., 1999). This method is rapid and sensitive, and it is a reliable parameter of total resorbed volume (including depth of pits).

Used herein is a method where osteoclast precursor cells derived from human bone marrow are cultured on bovine bone slices. The cells are first allowed to differentiate into mature bone-resorbing osteoclasts, and the formed osteoclasts are then allowed to resorb bone. The system is ideally suitable for determining the effects of test compounds on bone resorption in vitro. Test compounds are added into the cell cultures after the differentiation period, and their effect on the resorbing activity of mature osteoclasts is determined.

References Bagger YZ, Foged NT, Andersen L, Lou H, Qvist P (1999) CrossLaps for culture:
An improved enzyme-linked immunosorbent assay (ELISA) for measuring bone resorption in vitro. J Bone Miner Res 14, Suppl. 1, S370.

Boyde A, Ali NN, Jones SJ (1984) Resorption of dentine by isolated osteoclasts in vitro. Br Dent J 156: 216-220.

Chambers TJ, Revell PA, Fuller K, Athanasou NA (1984) Resorption of bone by isolated rabbit osteociasts. J Cell Sci 66: 383-399.

Hentunen TA, Lakkakorpi PT, Tuukkanen J, Lehenkari PP, Sampath TK, Vaananen HK (1995) Effects of recombinant human osteogenic protein-1 on the differentiation of osteociast-like cells and bone resorption. Biochem Biophys Res Commun 209:
433-443.

Laitala T, Vaananen HK (1994) Inhibition of bone resorption in vitro by antisense RNA and DNA molecules targeted against carbonic anhydrase II or two subunits of vacuolar H+-ATPase. J Clin Invest 93: 2311-2318.

Selander K, Lehenkari P, Vaananen HK (1994) The effects of bisphosphonates on the resorption cycle of isolated osteoclasts. Calcif Tissue Int 55: 368-375.

Sundquist K, Lakkakorpi P, Wallmark B, Vaananen HK (1990) Inhibition of osteoclast proton transport by bafilomycin A, abolishes bone resorption. Biochem Biophys Res Commun 168: 309-313.

Procedures Bone resorption assay The bone resorption assay is performed according to the above described Standard Operation Procedure. Shortly, human bone marrow-derived stem cells are suspended to culture medium and allowed to attach to bovine bone slices. The bone slices are transferred into 96-well tissue culture plates containing culture medium with appropriate amounts of important growth factors favoring osteoclast differentiation, including M-CSF, RANK-ligand and TGF-beta. The cells are incubated in a CO2 incubator in humidified atmosphere of 95% air and 5% carbon dioxide at 37 C. At day 7 when osteociast differentiation is completed, the culture medium is replaced with culture medium containing conditions favoring osteoclast activity, and the test compounds are added. The cell culture is continued for an additional three days, during which the formed mature osteociasts are allowed to resorb bone in the presence of vehicle, control inhibitor (E64) or test compounds at different concentrations. Tartrate-resistant acid phosphatase isoform 5b activity (TRACP
5b) is measured from the culture medium collected at day 7 using the BoneTRAP
assay (SBA-Sciences, Oulu, Finland). Medium TRACP 5b activity describes the number of osteoclasts formed in each well during the differentiation period.
At the end of the culture period, C-terminal cross-linked telopeptides of type I
collagen (CTX) released from the bone slices are quantitated as an index of bone resorption using CrossLaps for culture assay (Nordic Bioscience, Herlev, Denmark). The results are expressed as the resorption index (CTX at day 10/TRACP 5b at day 7), which describes the mean activity of a single osteoclast. When necessary, the ToxiLight assay (Cambrex, East Rutherford, NJ, USA) is used to detect cytotoxic effects of test compounds.

Statistical analysis The mean and standard deviation (SD) of each group is determined. One-way analysis of variance (ANOVA) is used to study if the values obtained between different groups (baseline vs. control and test compounds) are statistically different (with p < 0.05).

DESCRIPTION OF THE STUDY

This document contains results of preliminary testing of the effects of test compound EPO-477 on differentiation and activity of human osteoclasts. The test compound EPO-477 arrived to Pharmatest from Schering AG as a solid compound. 10 mM
stock solution was made by dissolving the compound at 5,43721 mg/ml in 96%
EtOH.
Appropriate dilutions were made from the stock solution to obtain the desired test concentrations (0,1 nM, 1 nM and 10 nM in osteoclast differentiation assay and 1 nM, 10 nM and 100 nM in osteoclast activity assay).

Two separate experiments were performed in this study, an osteociast differentiation assay and an osteoclast activity assay. In the osteociast differentiation assay, osteociast precursor cells were cultured for 7 days in the presence of the test compound, and TRACP 5b released into the culture medium was determined at day 7 as an index of the number of osteoclasts formed. Cytotoxicity was determined by quantitating the amount of dying cells from the culture medium at day 2. In the osteoclast activity assay, the test compounds were added after osteoclast differentiation was completed at day 7, and the mature osteoclasts were cultured for an additional 3 days, allowing them to resorb bone. Medium TRACP 5b was measured at day 7 to demonstrate the number of osteoclasts present in each well before adding the test compounds. Medium CTX was measured at day 10 to quantitate bone resorption during days 7-10, and the results are expressed as the resorption index CTX at day 10 / TRACP 5b at day 7, which describes the mean resorbing activity of a single osteoclast. Cytotoxicity was determined by quantitating the amount of dying cells from the culture medium at day 10.

One-way analysis of variance (ANOVA) was used to study if the values obtained between different groups were statistically different (with p<0.05). If a statistically significant difference was observed in ANOVA, the results of the test and control groups were compared separately with the results of the baseline group.

A) Osteoclast differentiation assay Table 1: The effects of test compound EPO-477 on the differentiation of human osteoclasts. The results are shown as medium TRACP 5b activity at day 7. The groups are: BL = Baseline (no added compounds); C = control (100 ng/ml OPG);
Al = 0,1 nM compound EPO-477; A2 = 1 nM compound EPO-477; A3 = 10 nM
compound EPO-477.

Replicate BL C Al A2 A3 1 21,91 4,46 14,72 9,20 2,88 2 23,66 10,67 16,43 9,20 3,02 3 10,40 10,53 21,41 8,25 2,34 4 22,06 10,19 17,57 7,59 2,15 5 17,71 5,70 17,37 7,52 1,93 6 17,46 10,00 21,95 7,84 2,41 Mean 18,87 8,59 18,24 8,27 2,45 SD 4,85 2,76 2,85 0,77 0,42 J

-- ***
LO 12 **

***

BL C Al A2 A3 Group Figure 1: The effects of test compound EPO-477 on the differentiation of human osteoclasts. The results are shown as medium TRACP 5b activity at day 7.
Figure 1 was prepared from the original data shown in Table 1 above. **p<0.01, ***p<0.001 5 compared with the baseline group. Compound EPO-477 inhibits dose-dependently the differentiation of human osteoclasts.

B) Osteoclast activity assay Table 3: The effects of test compound EPO-477 on the resorbing activity of human osteoclasts. The results are shown as CTX / TRACP 5b values. The CTX values were determined at the end of the resorption period at day 10, and the TRACP
5b values at the beginning of the resorption period at day 7. The groups are: BL
=
Baseline (no added compounds); C = control (1.0 M E64); Al = 1 nM compound EPO-477; A2 = 10 nM compound EPO-477; A3 = 100 nM compound EPO-477. The original CTX values are shown in table 5 and the original TRACP 5b values in table 6.

Replicate BL C Al A2 A3 1 2,78 0,41 3,32 0,79 0,87 2 3,17 0,64 4,36 1,45 0,92 3 2,74 0,41 3,20 0,84 0,56 4 2,84 0,38 2,98 1,00 0,89 5 4,01 0,59 3,09 1,93 0,36 6 2,62 0,29 2,90 0,82 1,07 Mean 3,03 0,45 3,31 1,14 0,78 SD 0,51 0,13 0,53 0,46 0,26 4,0 3,5 3,0 2,5 a 2,0 ***
H

U 1,0 ***
0,5 F T
0,0 BL C Al Group Figure 3: The effects of test compound EPO-477 on the resorbing activity of human osteoclasts. The results are shown as CTX / TRACP 5b values. Figure 3 was prepared from the original data shown in Table 3 above. ***p<0.001 compared with the baseline group. Compound EPO-477 inhibits dose-dependently the resorbing activity of human osteoclasts.

Table 4: Cytotoxic effects of test compound EPO-477 in human osteoclast activity assay. The results are shown as the luminescence released from dying cells during the culture period. The groups are: BL = Baseline (no added compounds); C =
control (1.0 M E64); Al = 1 nM compound EPO-477; A2 = 10 nM compound EPO-477; A3 = 100 nM compound EPO-477.

Replicate BL C Al A2 A3 Mean 1719 1594 1864 1957 2666 ***

= 2000 = 1500 .~

J

BL C Al A2 A3 Group Figure 4: Cytotoxic effects of test compound EPO-477 in human osteociast activity assay. The results are shown as the luminescence released from dying cells during the culture period. Figure 4 was prepared from the original data shown in Table 4 above. ***p<0.001 compared with the baseline group. Compound EPO-477 has dose-dependent cytotoxic effects in the human osteoclasts activity assay, and the inhibitory effects in Figure 3 are at least partly due to the observed cytotoxic effects.
However, 10 nM compound EPO-477 has no cytotoxic effects, although it significantly inhibited osteoclast activity.

Table 5: The effects of test compound EPO-477 on collagen degradation activity of human osteoclasts. The results are shown as the concentration of CTX (nM) released from bone collagen into the culture medium during the resorption phase (days 7-10). The groups are: BL = Baseline (no added compounds); C = control (1.0 M E64); Al = 1 nM compound EPO-477; A2 = 10 nM compound EPO-477; A3 =
100 nM compound EPO-477.

Replicate BL C Al A2 A3 1 46,28 9,13 56,56 10,31 15,63 2 68,09 10,96 68,03 31,82 14,51 3 63,78 7,91 54,94 15,76 11,55 4 57,91 7,78 58,62 16,61 16,48 5 74,20 9,39 61,84 29,41 6,70 6 59,07 5,45 62,04 17,07 15,83 Mean 61,56 8,44 60,34 20,16 13,45 SD 9,60 1,87 4,70 8,48 3,74 Table 6: Medium TRACP 5b activity (U/L) in each well at the beginning of the resorption phase at day 7. Secreted TRACP 5b activity describes the number of osteoclasts formed in each well during the differentiation period at days 1-7.
TRACP
5b was measured to determine the number of osteociasts in each well before adding the test compounds. The groups are: BL = Baseline (no added compounds); C =
control (1.0 M E64); Al = 1 nM compound EPO-477; A2 = 10 nM compound EPO-477; A3 = 100 nM compound EPO-477.

Replicate BL C Al A2 A3 1 16,66 22,20 17,04 13,00 17,90 2 21,47 17,13 15,61 21,94 15,85 3 23,25 19,27 17,16 18,73 20,51 4 20,38 20,75 19,64 16,53 18,46 5 18,52 16,04 20,02 15,20 18,52 6 22,57 18,92 21,37 20,80 14,78 Mean 20,48 19,05 18,47 17,70 17,67 SD 2,51 2,26 2,20 3,42 2,06 The above describes results were achieved by using 7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione as the test compounds.
The use of other epothilones in such tests [including, but not limited to Epothilone A, Epothilone B (also referred to as EPO-906), Epothilone C, Epothilone D (also referred to as Kos-862), Epothilone E and Epothilone F, BMS-247550, BMS-310705, ABJ-879, Fludelone, KOS-1584) shows similar results.

Example 2 Test compounds The test compounds used in this example are (1 S,3S,7S,10R,11 S,1 2S,1 6R)-7,1 1 -dihydroxy-3-(2-methyl-benzothiazol-5-yl)-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (referred to as EPO-477) and paclitaxel.
From test compound EPO-477 a 10 mM stock solution was made by dissolving 10 mg compound in 1.839 ml of 96% EtOH.
The test compound paclitaxel was used as a 5 mg/mI (5.855 mM) stock solution.
Paclitaxel is commercially available and is used for more than ten years for the treatment of cancer. Appropriate dilutions were made from the stock solutions to obtain the desired test concentrations; 2.5 nM, 5 nM, 7.5 nM, 10 nM, 15 nM, 20 nM
and 50 nM for compound EPO-477 and 2.5 nM, 5 nM, 10 nM, 20 nM, 50 nM, 100 nM
and 200 nM for compound paclitaxel in osteoclast activity assay Description of the study The test compounds were added after osteoclast differentiation was completed at day 7, and the mature osteoclasts were cultured for an additional 3 days, allowing them to resorb bone. Medium TRACP 5b was measured at day 7 to demonstrate the number of osteociasts present in each well before adding the test compounds.
Medium CTX was measured at day 10 to quantitate bone resorption during days 7-10, and the results are expressed as the resorption index CTX at day 10 /
TRACP 5b at day 7, which describes the mean osteoclast activity. Cytotoxicity was determined by quantitating the amount of dying cells from the culture medium at day 10.

One-way analysis of variance (ANOVA) was used to study if the values obtained between different groups were statistically different (with p<0.05). If a statistically significant difference was observed in ANOVA, the results of the test and control groups were compared separately with the results of the baseline group.

Summary of the results:

Table 7: Summary of the effects of test compounds EPO-477 and paclitaxel on activity and cytotoxicity of human osteociasts in vitro. The results are shown as % of activity compared with the results of the baseline group, the mean value of the baseline group being 100%. One asterisk (*) indicates a statistically significant difference with a p-value < 0.05 and two asterisks (**) with a p-value < 0.01.
NS =
Not significantly different from baseline.

Compound 2.5 nM 5 nM 7.5 nM 10 nM 15 nM 20 nM 50 nM

Resorbing 95 103 109 79 45 62 38 activity (NS) (NS) (NS) (NS) (**) (NS) (**) Cytotoxicity 98 96 91 96 79 78 85 (NS) (NS) (NS) (NS) (NS) (NS) (NS) Compound 2.5 nM 5 nM 10 nM 20 nM 50 nM 100 nM 200 nM
Paclitaxel Resorbing 109 98 87 95 64 57 72 activity (NS) (NS) (NS) (NS) (NS) (*) (NS) Cytotoxicity 121 99 121 116 131 120 125 (NS) (NS) (*) (NS) (**) (*) (*) = The compound EPO-477 inhibited significantly osteoclast activity and showed no cytotoxic effects.

= The compound paclitaxel showed mild inhibitory effects on osteoclast activity and significant cytotoxic effects.

Claims

1. Use of an Epothilone for the preparation of a medicament for the treatment, prevention or alleviation of diseases associated with a dysbalance of osteoblast and osteoclast activity.

2. Use according to claim 1 of an Epothilone for the preparation of a medicament for the treatment, prevention or alleviation of diseases associated with an activation of osteoclast activity causing the dysbalance of osteoblast and osteoclast activity.

3. Use of an Epothilone for the in-vitro or in-vivo inhibition of osteoclast activity.

4. Use of an Epothilone according to claim 1 for the preparation of a medicament for the treatment, prevention or alleviation of osteoporosis, osteonecrosis, osteoarthrosis, osteochondrosis, osteodystrophia.

5. Use according to claim 4 of an Epothilone for the preparation of a medicament for the treatment, prevention or alleviation of osteoporosis or related diseases.

6. Use of an Epothilone according to claim 1 for the for the preparation of a medicament for the treatment, prevention or alleviation of rheumatic diseases, Spondylitis, Lupus and related auto-imune diseases, padget disease, arthrosis, periodontal disease or inflammatory diseases leading to osteoclast hyperactivity or T-, B-, and NK killer cell mediated diseases.

7. Use according to claims 1, wherein the Epothilone is a naturally occuring Epothilone.

8. Use according to claim 7, wherein the Epothilone is naturally occuring Epothilone A, Epothilone B, Epothilone C, Epothilone D Epothilone E or Epothilone F.

9. Use according to any one of claims 1, wherein the Epothilone is a semi-synthetic or synthetic Epothilone derivative.

10. Use according to any one of claims 9, wherein the Epothilone is a compound of the general formula (I):

wherein R1a, R1b are each independently hydrogen, Cl-C10 alkyl, aryl, aralkyl, or together form a-(CH2)m-group where m is 2 to 5;

R2a, R2b are each independently hydrogen, Cl-C10 alkyl, aryl, aralkyl, or together form a-(CH2)n-group where n is 2 to 5, or are C2-C10 alkenyl or C2-C10 alkynyl;

R3 is hydrogen, Cl-C10 alkyl, aryl or aralkyl;

R4a, R4b are each independently hydrogen, C1-C10 alkyl, aryl, aralkyl, or together form a-(CH2)p-group where p is 2 to 5;

R5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2NH(alkyl), CH2N(alkyl)2, CH2NH(acyl), CH2N(acyl)2 or CH2HaI;

R6, R7 are each hydrogen, or together form an additional bond, or together form an epoxy function;

G is O or CH2;

D-E together is a group -H2C-CH2-, -HC=CH-, -C.ident.C-, -CH(OH)-CH(OH)-, -CH(OH)-CH2-, -CH2-CH(OH)-, -CH2-O-, -O-CH2-, or whereby if G is O then D-E is not CH2-O; or D-E-G together is a group H2C-CH=CH or a group CH=CH-CH2;

W is a group C(=X)R8, or is a bi- or tricyclic aromatic or heteroaromatic radical;

X is O, or two groups OR20, or a C2-C10 alkylenedioxy group (which may be straight or branched), or H and the group OR9, or a group CR10R11;

R 8 is hydrogen, C1-C10 alkyl, aryl, aralkyl, halogen, CN;
R9 is hydrogen or a protecting group PGX;

R10, R11 are each independently hydrogen, C1-C20 alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7-membered carbocyclic ring;
Z is O

or H and the group OR12;

R12 is hydrogen or a protecting group PGZ;

A-Y is a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O), or NR21-S02;
R20 is a C1-C20 alkyl group;

R21 is hydrogen, or C1-C10 alkyl;

PGx, PGz is C1-C20 alkyl, C4-C7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, C1-C20 acyl, aroyl, C1-C20 alkylsulfonyl, arylsulfonyl, tri(C1-C20 alkyl)silyl, di(C1-C20 alkyl) arylsilyl, (C1-C20 alkyl) diarylsilyl, or tri(aralkyl)silyl;

as a single stereoisomer or a mixture of different stereoisomers, and/or as a pharmaceutically acceptable salt thereof.

11. Use according to claim 10, wherein the Epothilone is a compound of formula (I) wherein R1a, R1b are each independently hydrogen, C1-C10 alkyl, aryl, aralkyl, or together form a-(CH2)m-group where m is 2 to 5;

R2a, R2b are each independently hydrogen, C1-C10 alkyl, aryl, aralkyl, or together form a-(CH2)n-group where n is 2 to 5, or are C2-C10 alkenyl or C2-C10 alkynyl;

R3 is hydrogen, C1-C10 alkyl, aryl or aralkyl;

R4a, R4b are each independently hydrogen, C1-C10 alkyl, aryl, aralkyl, or together form a-(CH2)p-group where p is 2 to 5;

R5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2NH(alkyl), CH2N(alkyl)2, CH2NH(acyl), CH2N(acyl)2 or CH2HaI;

R6, R7 are each hydrogen, or together form an additional bond, or together form an epoxy function;

G is O or CH2;

D-E together is a group -H2C-CH2-, -HC=CH-, -C.ident.C-, -CH(OH)-CH(OH)-, -CH(OH)-CH2-, -CH2-CH(OH)-, -CH2-O-, -O-CH2-, or whereby if G is O then D-E is not CH2-O; or D-E-G together is a group H2C-CH=CH or a group CH=CH-CH2;

W is a group C(=X)R8, or is a bi- or tricyclic aromatic or heteroaromatic radical;

X is O, or a group CR10R11;

R8 is hydrogen, C1-C10 alkyl, aryl, aralkyl, halogen, CN;

R10, R11 are each independently hydrogen, C1-C20 alkyl, aryl, aralkyl, or together with the methylene carbon form a 5- to 7-membered carbocyclic ring;

Z is O
or H and the group OR12;

R12 is hydrogen or a protecting group PGz;

A-Y is a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O), or NR21-S02;
R21 is hydrogen, or C1-C10 alkyl;

PGz is C1-C20 alkyl, C4-C7 cycloalkyl, which may contain one or more oxygen atoms in the ring, aryl, aralkyl, C1-C20 acyl, aroyl, C1-C20 alkylsulfonyl, arylsulfonyl, tri(C1-C20 alkyl)silyl, di(C1-C20 alkyl) arylsilyl, (C1-C20 alkyl) diarylsilyl, or tri(aralkyl)silyl;

as a single stereoisomer or a mixture of different stereoisomers, and/or as a pharmaceutically acceptable salt thereof.)

12. Use according to claim 11, wherein the Epothilone is a compound of the general formula (I):

wherein A-Y is O-C(=O);
D-E is H2C-CH2;
G is CH2;

Z is O;

R1a, R1b are both C1-C10 alkyl or together form a-(CH2)m,- group where m is 2 or 3;
R2a, R2b are each independently hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl;
R3 is hydrogen;

R4a, R4b are each independently hydrogen or C1-C10 alkyl;
R5 is C1-C10 alkyl.

13. Use according to claim 11, wherein R2a, R2b are each independently hydrogen, C2-C10 alkenyl or C2-C10 alkynyl;
R6, R7 together form an epoxy function or an additional bond; and W is a 2-Methyl-benzothiazol-5-yl radical, a 2-Methyl-benzoxazol-5-yl radical, or a Quinoline-7-yl radical.

14. Use according to claim 13, wherein the compound is selected from the group consisting of:

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-9,13-dimethyl-5,5-(1,3-trimethylen)-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2, 6-d ione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1,3-trimethylen)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(chinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(chinolin-2-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]
heptadecane-5,9-dione;

(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]
heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione; and (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.15. Use according to one of claims 11, wherein R2a, R2b are each independently hydrogen, or C1-C10 alkyl;

R6, R7 together form an epoxy function or an additional bond;
W is a group C(=X)R8;

X is a group CR10R11;

R8 is hydrogen, halogen, or C1-C10 alkyl; and R10, R11 are hydrogen/2-methyl-thiazol-4-yl, hydrogen/2-pyridyl, hydrogen/2-methylamine-thiazol-4-yl, or hydrogen/2-methylsulfanyl-thiazol-4-yl .
16. Use according to claim 15, wherein the compound is selected from the group consisting of:

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R, 12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-l3-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-l6-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-12,16-dimethyl-10-ethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-propyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-9,13-dimethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylen)-12,16-dimethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-(1,3-trimethylen)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-propyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-propyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(1,3-trimethylen)-7,9,13-trimethyl-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylen)-10,12,16-dimethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-chlor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-ethyl-cyclohexadec-13-ene-2,6-dione; and (1S/R,3S(Z),7S,10R,11S,12S,16R/S)-7,11-dihydroxy-3-(1-fluor-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-10-ethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

17. Use according to one of claims 11, wherein R2a, R2b are each independently hydrogen, C2-C10 alkenyl or C2-C10 alkynyl;
R6, R7 together form an epoxy function or an additional bond;

W is a group C(=X)R8;
X is a group CR10R11;

R8 is hydrogen, halogen, or C1-C10 alkyl; and R10, R11 are hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl.

18. The use of claim 17, wherein the compound is selected from the group consisting of:

(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1 S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(E),7S,10R,11R, 12S, 16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(1S/R,3S(E),7S,10R,11R, 12S, 16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

(1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S(Z),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S(Z))-4,8-dihydroxy-16-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione; and (1S/R,3S(Z),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione.

19. Use according to claim 11 wherein the Epothilone is selected from the group consisting of (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11S,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-9,13-dimethyl-5,5-(1,3-trimethylen)-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-12,16-dimethyl-8,8-(1,3-trimethylen)-4,17-dioxa bicyclo [14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;
(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(1,2-dimethyl-1H-benzoimidazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1,2-dimethyl-1H-benzoimidazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;

(1S/R,3S,7S,10R,11S,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-oxacyclohexadec-13-ene-2,6-dione , (4S,7R,8S,9S,10E,13Z,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-oxacyclohexadec-10,13-diene-2,6-dione, (4S,7R,8S,9S,10E,13Z,16S(E))-4,8-dihydroxy-5,5,7,9-tetramethyl-13-trifluormethyl-16-[1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-oxacyclohexadec-10,13-diene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-(2-methylsulfanyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione as a single stereoisomer or a mixture of different stereoisomers, and / or as a pharmaceutically acceptable salt thereof 20. Use according to one of claims 11, wherein A-Y is NR21-C(=O).

21. Use according to claim 11, wherein the epothilone is present in form of a pro-drug or an antibody conjugate.
22. Use according to claim 1, wherein the epothilone is formulated as tablets, capsules, granulates, suppositories, implantates, sterile injectable aqueous or oily solutions, suspensions or emulsions, aerosols, salves, creams, or gels, retard preparations, retard implantates, coated catheters or coated stents or wherein it is contained in an implantable dosing system.

23. A method of treating diseases associated with a dysbalance of osteoblast and osteoclast activity comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 7 to 20.

24. A method of treating osteoporosis or related diseases comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 7 to 20.

25. A method of treating diseases associated with an activation of osteoclast activity comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 7 to 20.

26. A method of treating osteoporosis, osteonecrosis, osteoarthrosis, osteochondrosis or osteodystrophia comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 7 to 20.

27. A method of treating treating, preventing or alleviating osteoporosis, osteonecrosis, osteoarthrosis, osteochondrosis or osteodystrophia comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 7 to 20.

28. A method of treating rheumatic diseases, Spondylitis, Lupus and related auto-immune diseases, padget disease, arthrosis, periodontal disease inflammatory diseases leading to osteoclast hyperactivity comprising administering to an individual in need thereof a therapeutically effective amount of an Epothilone as defined in any one of claims 7 to 20.

29. The use or the method according to any one of claims 1 to 28, wherein the Epothilone is to be administered orally, parenterally, intravenously;
rectally, or locally.

30. Use according to claim 1 in combination with an immunosuppressive agent.